This application is a 371 of PCT/JP99/02143, filed on Apr. 22, 1999.
The present invention relates to a medicine, especially to novel naphthalene derivatives having steroid C17,20-lyase inhibitory activity, or its production and pharmaceutical compositions containing the same.
It is known that, in the biosynthesis of androgen in vivo, steroid C17,20-lyase acts at the final stage. That is, steroid C17,20-lyase converts 17-hydroxypregnenolone and 17-hydroxyprogesterone derived from cholesterol to dehydroepiandrosterone and androstenedione, respectively. Therefore, a medicine having steroid C17,20-lyase inhibitory activity suppress the formation of androgen and estrogen which is produced from androgen, and is useful for preventing and treating diseases whose exacerbation factor is androgen or estrogen. As the disease whose exacerbation factor is androgen or estrogen, there may be mentioned, for example, prostate cancer, prostatic hypertrophy, virilism, irsutism, male pattern alopecia, precocious puberty, breast cancer, uterine cancer, mastopathy, uterus myoma, endometriosis, adenomyosis of uterus, polycystic ovary syndrome, etc.
It has been already known that some steroid type compounds and some non-steroid type compounds inhibit steroid C17,20-lyase. The steroid type compounds are disclosed in, for example, WO 92/15404, WO 93/20097, EP-A 288053, EP-A 413270, etc. As non-steroid type compounds, for example, (1H-imidazol-1-yl)methyl-substituted benzimidazole derivatives are shown in Japanese Published Unexamined Patent Application No.85975/1989, carbazole derivatives are shown in WO94/27989 and WO96/14090, azole derivatives are shown in WO95/09157, and 1H-benzimidazole derivatives are shown in U.S. Pat. No. 5,491,161.
Heretofore, steroid C17,20-lyase inhibitors which can actually be used as medicine have not been known. Thus, the early development of steroid C17,20-lyase inhibitors which are useful as medicine has been expected.
The present inventors have done extensive studies so as to find superior steroid C17,20-lyase inhibitors, and found that a compound having the formula (I) which has a naphthalene ring structure having nitrogen-containing heterocyclic groups through substituted methylene chain at 2-position unexpectedly has superior steroid C17,20-lyase inhibiting activity because of its specific structure and that the compound has less toxicity and has good properties as a medicine. The present invention has been accomplished by these findings.
Thus the present invention relates to
(1) A compound of the formula: 
xe2x80x83wherein A1 is an imidazolyl group, a thiazolyl group, an oxazolyl group or a pyridyl group, each of which may be substituted; R11 is a hydrogen atom, a hydrocarbon group which may be substituted; or a monocyclic aromatic heterocyclic group which may be substituted; R21 is a hydrogen atom or a lower alkyl group which may be substituted; R3, R4, R5, R6, R7, R8 and R9 are independently a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, a thiol group which may be substituted, an amino group which may be substituted, an acyl group or a halogen atom, provided (1) that R11 is a saturated hydrocarbon group which may be substituted when A1 is an oxazolyl group which may be substituted or a thiazolyl group which may be substituted, (2) that R7 is a hydroxy group which may be substituted or a lower alkyl group when A1 is a pyridyl group and R11 or R21 is a hydrogen atom and (3) that R21 is a lower alkyl group which may be substituted when R11 is a hydrogen atom, a salt thereof;
(2) A compound as shown in the above item (1), wherein R3, R4, R5, R6, R7, R8 and R9 are independently a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, an amino group which may be substituted, an acyl group or a halogen atom;
(3) A compound as shown in the above item (1), wherein R3, R4, R5, R6, R7, R8 and R9 are independently a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxy group which may be substituted or an acyl group;
(4) A compound as shown in the above item (1), wherein R3, R4, R5, R6, R7, R8 and R9 are independently a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, or a halogen atom;
(5) A compound as shown in the above item (1), wherein A1 is a 4- or 5-imidazolyl group which may be substituted or a 3- or 4-pyridyl group which may be substituted;
(6) A compound as shown in the above item (1), wherein A1 is a 4- or 5-imidazolyl group which may be substituted with {circle around (1)} a C1-4alkyl group unsubstituted or substituted with a C1-4alkanoyl, carboxyl, or a C1-4alkoxy-carbonyl, {circle around (2)} a C1-3alkoxy group, {circle around (3)} a C1-6alkanoyl {circle around (4)} C1-4alkylsulfonyl, {circle around (5)} carbamoyl, a mono- or di-C1-10alkyl carbamoyl group, a mono- or di-C6-14arylcarbamoyl group or a mono- or di-C7-16aralkylcarbamoyl group, or {circle around (6)} sulfamoyl, a mono- or di-C1-10alkyl sulfamoyl group, a mono- or di-C6-14arylsulfamoyl group, or a mono- or di-C7-16aralkyl sulfamoyl group;
(7) A compound as shown in the above item (1), wherein A1 is a 3- or 4-pyridyl group which may be substituted with {circle around (1)} a C1-4alkyl group unsubstituted or substituted with a C1-4alkanoyl, carboxyl, or a C1-4alkoxy-carbonyl, {circle around (2)} a C1-3alkoxy group, {circle around (3)} a C1-6alkanoyl {circle around (4)} C1-4alkylsulfonyl, {circle around (5)} carbamoyl, a mono- or di-C1-10alkyl carbamoyl group, a mono- or di-C6-14arylcarbamoyl group or a mono- or di-C7-16aralkylcarbamoyl group, or {circle around (6)} sulfamoyl, a mono- or di-C1-10alkyl sulfamoyl group, a mono- or di-C6-14arylsulfamoyl group, or a mono- or di-C7-16aralkyl sulfamoyl group;
(8) A compound as shown in the above item (1), wherein A1 is a thiazolyl group which may be substituted;
(9) A compound as shown in the above item (1), wherein R21 is a hydrogen atom or a lower alkyl group;
(10) A compound as shown in the above item (1), wherein R21 is a hydrogen atom;
(11) A compound as shown in the above item (1), wherein one to three groups of R3, R4, R5, R6, R7, R8 and R9 are independently a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, an amino group which may be substituted, an acyl group or a halogen atom;
(12) A compound as shown in the above item (1), wherein one to three groups of R3, R4, R5, R6, R7, R8 and R9 are independently a C1-6alkyl group which may be substituted, a hydroxy group which may be substituted or a C1-6acyl group;
(13) A compound as shown in the above item (1), wherein R11 is a hydrogen atom, a lower alkyl group which may be substituted, a phenyl group which may be substituted or a pyridyl group which may be substituted;
(14) A compound as shown in the above item (1), wherein R11 is a hydrogen atom, a lower alkenyl group, a cyclic alkyl group, a phenyl group, a pyridyl group, or a lower alkyl group which may be substituted with halogen atom(s);
(15) A compound as shown in the above item (1), wherein R11 is an C1-6alkyl group and R21 is a hydrogen atom;
(16) A compound as shown in the above item (1), wherein R11 is an isopropyl group and R21 is a hydrogen atom;
(17) A compound as shown in the above item (1), wherein R7 is a hydroxy group which may be substituted or a lower alkyl group;
(18) A compound as shown in the above item (1), wherein R7 is (1) a hydroxy group which may be substituted with a lower alkanoyl group, a lower alkanoyloxy-lower alkyl group, a lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkyl group which may have one to 4 halogen atoms (e.g. fluorine atoms), or a benzyl group, (2) a halogen atom, (3) a lower alkyl group which may be substituted with a hydroxy group, (4) a lower alkynyl group, (5) a lower alkanoyl group, (6) an amino group which may be substituted with a lower alkanoyl group, a lower alkylaminocarbonyl group or a lower alkylsulfonyl group, or (7) a lower alkylthio group;
(19) A compound as shown in the above item (1), wherein R7 is a lower alkyl group, a lower alkoxy group or a lower alkanoylamino group;
(20) A compound as shown in the above item (1), wherein R7 is a methoxy group;
(21) A compound as shown in the above item (1), wherein R8 is a hydrogen atom, a lower alkyl group or a lower alkoxy group;
(22) A compound as shown in the above item (1), wherein R8 is a hydrogen atom or a lower alkoxy group;
(23) A compound as shown in the above item (1), wherein R6 is (1) a hydrogen atom (2) a halogen atom (3) a lower alkoxy group or (4) a lower alkyl group which may be substituted with a hydroxy group;
(24) A compound as shown in the above item (1), wherein R6 is a hydrogen atom or a lower alkyl group;
(25) A compound as shown in the above item (1), wherein one of R6, R7 and R8 is a lower alkyl group or a lower alkoxy group;
(26) A compound as shown in the above item (1), wherein each of R3, R4, R5 and R9 is a hydrogen atom;
(27) A prodrug of a compound shown in the above item (1);
(28) A compound as shown in the above item (1), which is 1-(1H-imidazol-4-yl-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol, 1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol, 1-(6-methoxy-5-methylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol, N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}acetamide or 1-(6-ethylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol or a salt thereof;
(29) A pharmaceutical composition containing a compound shown in the above item (1) or prodrug shown in the above item (27);
(30) A steroid C17,20-lyase inhibitory composition containing a compound of the formula: 
xe2x80x83wherein A is a nitrogen-containing heterocyclic group which may be substituted, R1 is a hydrogen atom, hydrocarbon group which may be substituted, or monocyclic aromatic heterocyclic group which may be substituted, R2 is a hydrogen atom or a lower alkyl group which may be substituted, R3, R4, R5, R6, R7, R8 and R9 are independently a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, a thiol group which may be substituted, an amino group which may be substituted, an acyl group or a halogen atom, a salt thereof or a prodrug thereof;
(31) A composition as shown in the above item (30), which is an antitumor agent;
(32) A composition for an antitumor agent as shown in the above item (1), wherein the antitumor agent is a treating or preventing breast cancer or prostate cancer;
(33) A method for treating or preventing a disease whose exacerbation factor is androgen or estrogen, which comprises administering an effective amount of a compound of the formula (Ixe2x80x2), a salt thereof or a prodrug thereof, optionally together with a pharmaceutically acceptable carrier, diluent or excipient, to a patient suffering from the disease;
(34) A method for treating or preventing a disease whose exacerbation factor is androgen or estrogen, which comprises administering an effective amount of a compound of the formula (I), a salt thereof or a prodrug thereof, optionally together with a pharmaceutically acceptable carrier, diluent or excipient, to a patient suffering from the disease;
(35) A method as shown in the above item (34) wherein the diseases whose exacerbation factor is androgen or estrogen is a cancer;
(36) A method as shown in the above item (34), wherein the cancer is breast cancer or prostate cancer;
(37) Use of a compound of the formula (Ixe2x80x2) a salt thereof or a prodrug thereof for the production of a pharmaceutical composition;
(38) Use of a compound of the formula (I) a salt thereof or a prodrug thereof for the production of a steroid C17,20-lyase inhibitory composition;
(39) Use as shown in the above item (38), wherein the composition is for treating or preventing a cancer;
(40) Use as shown in the above item (38), wherein the composition is for treating or preventing of breast cancer or prostate cancer;
(41) A compound of the formula: 
xe2x80x83wherein A2 is an imidazolyl group which may be substituted, R3, R4, R5, R6, R7, R8 and R9 are independently a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, a thiol group which may be substituted, an amino group which may be substituted, an amino group which may be substituted, an acyl group or a halogen atom, or a salt thereof;
(42) A process for producing a compound of the formula: 
xe2x80x83wherein A3 is an imidazolyl group, a thiazolyl group or an oxazolyl group, each of which may be substituted, R3, R4, R5, R6, R7, R8 and R9 are independently a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, a thiol group which may be substituted, an amino group which may be substituted, an acyl group or a halogen atom, and R12 is a hydrocarbon group which may be substituted, or a monocyclic aromatic heterocyclic group which may be substituted, or a salt thereof, which comprises reacting a compound of the formula: 
xe2x80x83wherein each symbol has the same meaning as defined above, or a salt thereof with a compound of the formula:
R12xe2x80x94Mxe2x80x83xe2x80x83(III)
xe2x80x83wherein M is a metal or a salt thereof and R12 has the same meaning as defined above.
In the above formulas, as the xe2x80x9cnitrogen-containing heterocyclic groupxe2x80x9d in the xe2x80x9cnitrogen-containing heterocyclic group which may be substitutedxe2x80x9d shown by A, there may be mentioned a nitrogen-containing aromatic heterocyclic group, a saturated or unsaturated nitrogen-containing non-aromatic heterocyclic group (a nitrogen-containing aliphatic heterocyclic group) having at least a nitrogen atom as the ring constituting atoms, preferably a nitrogen-containing aromatic heterocyclic group. As the nitrogen-containing aromatic heterocyclic group, there may be mentioned a nitrogen-containing 5- or 6-membered aromatic heterocyclic group such as imidazolyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl. Among them, imidazolyl, pyridyl, thiazolyl, oxazolyl, etc., are preferable and 4 or 5-imidazolyl group and 3 or 4-pyridyl group are the most preferable.
In the xe2x80x9cnitrogen-containing aromatic heterocyclic group which may be substitutedxe2x80x9d shown by A, one to three substituents may be substituted at any position on the nitrogen-containing aromatic heterocyclic group. As the substituent, there may be mentioned a lower alkyl group which may be substituted, a lower alkoxy group, an acyl group, etc. Examples of the lower alkyl which may be substituted include, an unsubstituted C1-4alkyl group such as methyl, ethyl, propyl, etc., and an C1-4alkyl group substituted by an C1-4alkanoyl such as acetyl, propionyl, etc., carboxyl, a C1-4alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc.), etc. As the lower alkoxy group, there maybe mentioned, for example, a C1-3alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, etc. As the acyl group, there may be mentioned, for example, an alkanoyl group (e.g. such a C1-6alkanoyl as formyl, acetyl, propionyl, etc.), an alkylsulfonyl group (e.g. such a C1-4alkylsulfonyl as methylsulfonyl, ethylsulfonyl, etc.), a carbamoyl group which may be substituted (e.g. such a mono- or di-C1-10alkyl carbamoyl group as methylcarbamoyl, ethylcarbamoyl, dimeothylcarbamoyl, diethylcarbamoyl, etc., such a mono- or di-C6-14arylcarbamoyl as phenylcarbamoyl, diphenylcarbamoyl, etc., such a mono- or di-C7-16aralkylcarbamoyl group as benzylcarbamoyl, dibenzylcarbamoyl, etc.), a sulfamoyl which may be substituted (e.g. such a mono- or di-C1-10alkyl sulfamoyl group as methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, etc., such a mono- or di-C6-14arylsulfamoyl group as phenylsulfamoyl, diphenylsulfamoyl, etc., such a mono- or di-C7-16aralkyl sulfamoyl group as benzylsulfamoyl, dibenzylsulfamoyl, etc.), etc.
The imidazolyl group which may be substituted, the thiazolyl group which may be substituted, the oxazolyl group which may be substituted and the pyridyl group which may be substituted, represented by A1 have the same meaning as the imidazolyl group which may be substituted, the thiazolyl group which may be substituted, the oxazolyl group which may be substituted and the pyridyl group which may be substituted, respectively, each of which may be mentioned in the definition of the nitrogen-containing heterocyclic group which may be substituted represented by A. The preferable examples of A1 are the preferable examples mentioned in the definition of A and included in the definition of A1.
The imidazolyl group which may be substituted represented by A2 has the same meaning as the imidazolyl group which may be substituted which may be mentioned in the definition of the nitrogen-containing heterocyclic group which maybe substituted represented by A. The preferable examples of A2 are the preferable examples mentioned in the definition of A and included in the definition of A2.
The imidazolyl group which may be substituted, the thiazolyl group which may be substituted and the oxazolyl group which may be substituted, represented by A3 have the same meaning as the imidazolyl group which may be substituted, the thiazolyl group which may be substituted and the oxazolyl group which may be substituted, which may be mentioned in the definition of the nitrogen-containing heterocyclic group which may be substituted represented by A. The preferable examples of A2 are the preferable examples mentioned in the definition of A and included in the definition of A3.
Examples of the hydrocarbon group in the definition of xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d shown by R1 include, for example, an aliphatic hydrocarbon group, a cyclic hydrocarbon group, etc. Examples of the aliphatic hydrocarbon group include, for example, a straight chain or branched aliphatic hydrocarbon group having 1 to 10 carbon atoms such as an alkyl group, an alkenyl group, etc. Among them, an alkyl group is preferable. Examples of the alkyl group include, for example, a C1-10alkyl group, such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, etc. Among them, a C1-6alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.) is preferable. Examples of the alkenyl group include, for example, a C2-10alkenyl group such as vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, sec-butenyl, etc. Among them, a C2-6alkenyl group (for example, vinyl, 1-propenyl, allyl, etc.) is preferable. Examples of the alkynyl group include, for example, a C2-10alkynyl group such as ethynyl, 1-propynyl, propargyl, etc. is preferable. Among them, a C2-6alkynyl group (for example, ethynyl, etc.) is preferable.
Examples of the cyclic hydrocarbon group are one having 3 to 18 carbon atoms and include, for example, an aliphatic cyclic hydrocarbon group, an aromatic hydrocarbon group, etc. Examples of the aliphatic cyclic hydrocarbon group include, for example, a monocyclic or condensed polycyclic group consisting of 3 to 10 carbon atoms. Examples of the embodiment include a cycloalkyl group, a cycloalkenyl group, a bi- or tri-cyclic condensed ring formed by condensing one of them with a C6-14aryl group (for example, benzene, etc.), etc. Examples of the cycloalkyl group include, for example, a C3-6cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of the cycloalkenyl group include, for example, a C3-6cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentehyl, cyclohexenyl, etc.
Examples of the aromatic hydrocarbon group include a monocyclic aromatic hydrocarbon group, a condensed polycyclic aromatic hydrocarbon group, etc., each of which is constituted with 6 to 18 carbon atoms. Examples of the embodiment include a C6-14aryl group such as phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, etc. Among them, a C6-10aryl group (for example, phenyl, etc.) is preferable. Examples of the substituent which substitutes on the aliphatic hydrocarbon group in the definition of xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d are not limited but include, for example, a halogen atom, a hydroxy group, an alkoxy group, an acyloxy group, an alkylthio group, an acylamino group, a carboxyl group, an alkoxycarbonyl group, an oxo group, an alkylcarbonyl group, a cycloalkyl group, an aryl group, an aromatic heterocyclic group, etc. These substituents may substitute on the aliphatic hydrocarbon group in a chemically acceptable range. The number of the substituent is usually 1 to 5 and preferably 1 to 3. When the number of substituents is more than two, the substituents may be the same or different from each other.
Examples of the substituent which substitutes on the cyclic hydrocarbon group in the definition of xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d are not limited but include, for example, a halogen atom, a hydroxy group, an alkoxy group, an acyloxy group, an alkylthio group, an alkylsulfonyl group, a mono- or dialkylamino group, an acylamino group, a carboxyl group, an alkoxycarbonyl group, an alkynylcarbonyl group, an alkyl group, a cycloalkyl group, an aryl group, an aromatic heterocyclic group, etc.
These substituents may substitute on the aliphatic hydrocarbon group in a chemically acceptable range. The number of the substituents is usually 1 to 5 and preferably 1 to 3. When the number of substituents is more than two, the substituents may be the same or different from each other.
Examples of the halogen atom include fluorine, chlorine, bromine, iodine.
Examples of the alkoxy group include, for example, a C1-10alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc. Examples of the acyloxy group include, for example, formyloxy, a C1-10alkyl-carbonyloxy (for example, acetoxy, propionyloxy, etc.), etc. Examples of the alkylthio group include, for example, a C1-10alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, etc. Examples of the alkylsulfonyl group include, for example, a C1-10alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc. Examples of the acyl amino group include, for example, formylamino, diformylamino, a mono- or di-C1-10alkyl-carbonylamino (for example, acetylamino, propionylamino, butyrylamino, diacetylamino, etc.), etc. Examples of the alkoxycarbonyl group include, for example, a C1-10alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, etc. Examples of the alkylcarbonyl group include, for example, a C1-10alkylcarbonyl group such as acetyl, propionyl, butyryl, valeryl, etc. Examples of the alkynylcarbonyl group include for example, a C3-10alkynylcarbonyl group, such as acetylenylcarbonyl, 1-propynylcarbonyl, 2-propynylcarbonyl, etc.
Examples of the cycloalkyl group include, for example, a C3-10cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of the aryl group include, for example, a C6-14aryl group such as phenyl, 1-naphthyl, 2-naphthyl, etc. Examples of the aromatic heterocyclic group include, for example, a mono- to tri-cyclic aromatic heterocyclic group containing one or two kinds of hetero atoms and preferably 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur. Examples of the embodiment include, for example, thienyl, pyridyl, furyl, pyrazinyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridazinyl, tetrazolyl, quinolyl, indolyl, isoindolyl, etc. Examples of the alkyl group include, for example, a C1-10alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, etc.
Examples of the substituent which substitutes on the hydrocarbon group mentioned above also include the following substituents, the number of the substituents is 1 to 5, preferably 1 to 3. Examples of the substituents include, for example, a halogen atom (for example, fluorine, chlorine, bromine, etc.), a hydroxy group, C1-6alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, etc.), etc.
Examples of the monocyclic aromatic heterocyclic group in the definition of xe2x80x9cmonocyclic aromatic heterocyclic group which may be substitutedxe2x80x9d shown by R1 include, for example, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 3-pyridazinyl, etc. Among them, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-imidazolyl, 4-imidazolyl, etc., are preferable.
The substituent of xe2x80x9cmonocyclic aromatic heterocyclic group which may be substitutedxe2x80x9d in the definition R1 may substitute at the substitutable position of the monocyclic aromatic heterocyclic group. The number of the substituents is 1 to 3. Examples of the substituents include an alkyl group which may be substituted by 1 to 5 halogen atoms (e.g. fluorine, chlorine, bromine, iodine) (e.g. such a C1-4alkyl as methyl, ethyl, propyl, etc., such a C1-4alkyl substituted by halogen as 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,etc.), a C1-3alkyl group such as methyl, ethyl, propyl, isopropyl, etc., a C1-3alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, etc., a halogen atom such as a chlorine atom, a fluorine atom, etc., a hydroxy group, an amino group, a nitro group, etc.
The preferable Examples of R1 include a hydrogen atom, a lower(C1-4)alkyl group which may be substituted, a lower(C1-14)alkenyl group, a cyclic(C3-6)alkyl group, a phenyl group which may be substituted and a pyridyl group which may be substituted each of which is mentioned above. Among them, a hydrogen atom, a lower(C1-4)alkenyl group, a cyclic(C3-6)alkyl group, a phenyl group, a pyridyl group and a lower(C1-14)alkyl group which may be substituted with halogen(s) are the most preferable.
The saturated hydrocarbon group which may be substituted and the monocyclic aromatic heterocyclic group which may be substituted represented by R11 have the same meaning as the hydrocarbon group which may be substituted and the monocyclic aromatic heterocyclic group which may be substituted, mentioned in the definition of R1 and included in the definition of R11. The preferable examples of R11 are the preferable examples mentioned in the definition of R1 and included in the definition of R11.
The saturated hydrocarbon group which may be substituted and the monocyclic aromatic heterocyclic group which may be substituted represented by R12 have the same meaning as those mentioned in the definition of R1.
Examples of the lower alkyl group shown by R2 include a straight chain or cyclic C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, hexyl, etc.) which may be substituted. The C1-6alkyl group may be substituted by 1 to 5 substituents at any position. Examples of the substituents include, for example, a halogen (e.g. fluorine, chlorine, bromine, etc.), a C1-4alkoxy group (e.g. methoxy, ethoxy, propoxy, etc.), etc.
Preferable examples of R2 include a hydrogen atom and a non-substituted lower(C1-6)alkyl group among the lower alkyl group mentioned above, and a hydrogen atom is the most preferable.
The lower alkyl group which may be substituted represented by R21 has the same meaning as that mentioned in the definition of R2.
The preferable examples of R21 are the preferable examples mentioned in the definition of R21 and an included in the definition of R21.
Examples of the hydroxy group which may be substituted shown by R3, R4, R5, R6, R7, R8, R9 include an unsubstituted hydroxy group, a lower alkoxy (e.g. a C1-4alkoxy group such as methoxy, ethoxy, propoxy, etc.), a lower alkanoyloxy (e.g. a C1-4alkanoyloxy such as acetyloxy, propionyloxy, etc.), a carbamoyloxy which may be substituted (e.g. unsubstituted carbamoyloxy, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy, methylethylcarbamoyloxy, etc., a carbamoyloxy substituted by 1 or 2 C1-4alkyl group), etc.
Examples of the thiol group which may be substituted shown by R3, R4, R5, R6, R7, R8, R9 include unsubstituted thiol group, a lower alkylthio (e.g. a C1-4alkylthio group such as methylthio, ethylthio, propylthio, etc.), a lower alkanoylthio (e.g. a C1-4alkanoylthio such as acetylthio, propionylthio, etc.), etc.
Examples of the amino group which may be substituted shown by R3, R4, R5, R6, R7, R8, R9 include an unsubstituted amino group, a lower alkylamino (e.g. a C1-4alkyl amino group such as methylamino, ethylamino, propylamino, etc.), a di-lower alkylamino (e.g. a di-C1-4alkylamino such as dimethylamino, diethylamino, etc.), a C1-4alkanoylamino (e.g. acetamide, propionamide, etc.), etc.
Examples of the acyl group represented by R3, R4, R5, R6, R7, R8 or R9 include, for example, an alkanoyl group (e.g. formyl, a C1-6alkanoyl such as acetyl, propionyl, etc.), an alkylsulfonyl group (e.g. C1-4alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc.), a carbamoyl group (mono- or di-C1-10alkyl carbamoyl group such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc., a mono- di-C6-14arylcarbamoyl group such as phenylcarbamoyl, diphenylcarbamoyl, etc., a mono- di-C7-16aralkyl carbamoyl group such as benzylcarbamoyl, dibenzylcarbamoyl, etc.), a sulfamoyl group which may be substituted (a mono- or di-C1-10alkylsulfamoyl group such as methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, etc., a mono- or di-C6-14arylsulfamoyl group such as phenylsulfamoyl, diphenylsulfamoyl, etc., a mono- or di-C7-16aralkyl sulfamoyl group such as benzylsulfamoyl, dibenzylsulfamoyl, etc.), etc.
Examples of the halogen shown by R3, R4, R5, R6, R7, R8, R9 include fluorine, chlorine, bromine, iodine.
Examples of the hydrocarbon group which may be substituted shown by R3, R4, R5, R6, R7, R8, R9 include the same one as the hydrocarbon group which may be substituted shown by R1. Among them, a lower alkyl group which may be substituted is preferable. Examples of the embodiment include a straight or cyclic C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, hexyl, etc.) which may be substituted. The C1-6alkyl group may be substituted by 1 to 5 substituents at any position. Examples of the substituent include, for example, a halogen (e.g. fluorine, chlorine, bromine, etc.), a C1-4alkoxy group (e.g. methoxy, ethoxy, propoxy, etc.), a hydroxy group, etc. Examples of the lower alkoxy group which may be substituted include methoxy, ethoxy, propoxy, etc. The lower alkoxy group may be substituted by 1 to 5 substituents at any position. Examples of the substituents include, for example, a halogen (e.g. fluorine, chlorine, bromine, etc.), C1-4alkoxy group (e.g. methoxy, ethoxy, propoxy, etc.), etc. Preferable example of R3, R4, R5, R6, R7, R8 or R9 include, for example, a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, an amino group which may be substituted, a C1-6acyl group or a halogen atom each of which is mentioned above, and among them, a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, an acyl group and a halogen atom are more preferable.
As R7, a hydroxy group which may be substituted and a lower alkyl group are preferable, and (1) a hydroxyl group which may be substituted with a lower alkanoyl group, a lower alkanoyloxy-lower alkyl group, a lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkyl group having 1 to 4 fluorine atoms or a benzyl group, (2) a halogen atoms, (3) a lower alkyl group which may be substituted with a hydroxyl group, (4) a lower alkynyl group, (5)a lower alkanoyl group, (6)an amino group which may be substituted with a lower alkanoyl group, a lower alkylaminocarbonyl group or a lower alkylsulfonyl group, or (7) a lower alkylthio group is more preferable. Among them, a lower alkyl group, a lower alkoxy group and a lower alkanoylamino group are more preferable and a methoxy group is the most preferable.
As R8, hydrogen atom, a lower alkyl group and a lower alkoxy are preferable and hydrogen atom and a lower alkoxy are more preferable. As R6, (1) a hydrogen atom, (2) halogen atom, (3) a lower alkoxy group and (4) a lower alkyl group which may be substituted with a hydroxyl group are preferable, and a hydrogen atom and a lower alkyl group are more preferable.
It is preferable that one to three groups selected from the group consisting of R3, R4, R5, R6, R7, R8 and R9 are independently a lower alkyl group which may be substituted, a hydroxyl group which may be substituted, an amino group which may be substituted, an acyl group or a halogen atom.
It is more preferable that one to three groups selected from the group consisting of R3, R4, R5, R6, R7, R8 and R9 are independently a lower alkyl group which may be substituted, a hydroxyl group which may be substituted or a C1-6acyl group.
It is preferable that one of R6, R7 and R8 is a lower alkyl group or a lower alkoxy group, and each of R3, R4, R5 and R9 is a hydrogen atom.
Among Compound (I), a compound wherein R1 is a C1-6alkyl group and R21 is a hydrogen atom is preferable, and a compound wherein R11 is an isopropyl group and R21 is a hydrogen atom is more preferable.
The preferable examples of the compound shown by the formula (I) include, for example, the compound of the formula 
(wherein each of R1, R2, R3, R4, R5, R6, R7, R8 and R9 has the meanings shown above). Preferable examples of the embodiments include, for example, 1-(1H-imidazol-4-yl-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol, 1-(6,7-dimethoxynaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol, 1-(6-methoxy-5-methylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol, N-{6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]naphthalen-2-yl}acetamide, 1-(6-ethylnaphthalen-2-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol and salts thereof or prodrugs thereof.
The compound of the formula (I) may be a salt. Examples of the salt include a salt of inorganic acid (for example, a hydrochloric acid salt, a sulfuric acid salt, a hydrobromic acid salt, a phosphoric acid salt, etc.), a salt of an organic acid (for example, an acetic acid salt, a trifluoroacetic acid salt, a succinic acid salt, a maleic acid salt, a fumaric acid salt, a propionic acid salt, a citric acid salt, a tartaric acid salt, a lactic acid salt, an oxalic acid salt, a methane sulfonic acid salt, a p-toluenesulfonic acid salt, etc.), etc., a salt with a base (for example, salt with an alkali metal such as a potassium salt, a sodium salt, a lithium salt, etc., an alkaline earth metal salt such as a calcium salt, a magnesium salt, etc., an ammonium salt, a salt with an organic base such as a trimethylamine salt, a triethyl amine salt, tert-butyldimethylamine salt, a dibenzylmethylamine salt, a benzyldimethylamine salt, a N,N-dimethylaniline salt, a pyridine salt, a quinoline salt, etc.).
The compound shown by (I) or a salt thereof may be a hydrate. Hereinafter these are referred to as Compound (I).
The pro-drug of Compound (I) means a compound which is converted to compound (I) having steroid C17,20-lyase inhibitory activity by enzymes, gastric acid, etc. in vivo.
Examples of the pro-drug of a compound (I) include a compound wherein an amino group of Compound (I) is substituted with acyl, alkyl phosphoric acid, etc. (e.g. a compound wherein an amino group of Compound (I) is substituted with eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, tert-butyl, etc.); a compound wherein an hydroxy group of Compound (I) is substituted with acyl, alkyl, phosphoric acid, boric acid, etc. (e.g. a compound wherein an hydroxy group of Compound (I) is substituted with acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl, dimethylaminomethylcarbonyl, etc.); a compound wherein a carboxyl group of Compound (I) is modified with ester, amide, etc. (e.g. a compound wherein a carboxyl group of Compound (I) is modified with ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester, cyclohexyloxycarbonylethyl ester, methyl amide, etc.); etc. These pro-drugs can be produced by per se known methods.
The pro-drug of Compound (I) may be a compound which is converted into Compound (I) under the physiological conditions as described in xe2x80x9cPharmaceutical Research and Developmentxe2x80x9d, Vol. 7 (Drug Design), pages 163-198 published in 1990 by Hirokawa Publishing Co. (Tokyo, Japan).
The compound (I) or a pro-drug thereof may be in the form of any pharmaceutically acceptable salts thereof. Examples of said salts include a salt with inorganic bases (e.g., alkaline metals such as sodium, potassium, etc.; alkaline earth metals such as calcium, magnesium, etc.; transition metal such as zinc, iron, copper, etc.; etc.); organic bases (e.g., organic amines such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine, etc.; basic amino acids such as arginine, lysine, ornithine, etc.; etc.); etc., when said compound (I) has an acidic group such as a carboxyl group, etc.; and a salt with inorganic acids ororganic acids (e.g., hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.); acidic amino acids such as aspartic acid, glutamic acid, etc.; etc., when said compound (I) has a basic group such as an amino group, etc.
Also, Compound (I) may behydtated.
Compound (I) may have one or more asymmetric carbons in the molecule. The compound of the present invention may have R-configuration or S-configuration as to the asymmetric carbons.
The xe2x80x9clowerxe2x80x9d in xe2x80x9ca lower alkyl groupxe2x80x9d, xe2x80x9ca lower alkoxy groupxe2x80x9d, etc., throughout the present specification means a straight, branched or cyclic ones having 1 to 6 carbon otherwise mentioned.
In the present application, the compounds of the formulas (Ixe2x80x2), (Ia), (Ib) and (Ic) are included in the compounds of the formula (I), and the compounds of the formula (IIxe2x80x2) are included in the compounds of the formula (II). Among the compound shown by the formulas (Ia), (Ib), (Ic), (II), (IIxe2x80x2), (III), (IVa), (IVb), (IVc1), (IVc2), (IVd), (IVe1), (IVe2), (IVf), (Vb), (Vd), (VIa), (VIb), (VIc), (VId), (VIe) (VIf), (VIg), (VIIa), (VIIb) and (VIIc), compounds having a basic group or an acidic group can form a salt with acid or a salt with base, respectively. Examples of the salts include the salts of the compound (I) mentioned above. Hereinafter the compound of the formula (Number of formula) and its salt are referred to as Compound (Number of formula). For example, both a compound of formula (IVa) and a salt thereof are referred to as Compound (IVa).
Compound (I) can be produced, for example, by the following process steps.
The starting compound and an intermediate can be used as free form or a salt thereof like Compound (I). The reaction mixture as it is or after isolation by a known method can be used for the following reaction. 
[wherein X is a halogen atom, L is a leaving group (e.g. a halogen atom, an alkyl or aryl sulfonyloxy group, etc.), R22 is a lower alkyl group which may be substituted, A11 is a nitrogen-containing heterocyclic group which may be protected or/and substituted, and each of the other symbols has the same meaning as defined above.]
Examples of the nitrogen-containing heterocyclic group which may be substituted in the definition of xe2x80x9cnitrogen-containing heterocyclic group which may be protected or/and substituted shown by A11 include the same as that mentioned above, and the protecting group is the same as that mentioned below.
Examples of the metal shown by M include lithium or magnesium, etc. Examples of the salt of metal shown by M include, for example, a metal halide such as magnesium chloride, magnesium bromide, etc.
The compound (IVa) is allowed to react with alkyl lithium or magnesium metal, etc., to give an organometal compound (IVb). The compound (IVb) is allowed to react with an aldehyde (IVe1) or (IVe2) to give a compound (IVc1) or (IVc2), respectively. Examples of the alkyl lithium used include a C1-4alkyl lithium such as n-butyl lithium, s-butyl lithium, etc. The alkyl lithium is used in an amount of 1 to 3 moles, preferably 1 to 1.5 moles per one mole of the starting material (IVa). The reaction temperature in case of the reaction with alkyl lithium is in the range of xe2x88x92100xc2x0 C. to 0xc2x0 C., preferably xe2x88x9280xc2x0 C. to xe2x88x9220xc2x0 C. The temperature in case of the reaction with magnesium metal is in the range of xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 10xc2x0 C. to 50xc2x0 C. The reaction time is about 5 min to 20 h. The reaction is usually carried out in the presence of an organic solvent which does not affect to the reaction. Examples of the organic solvent which does not affect to the reaction include, for example, an ether such as diethyl ether, dioxane, tetrahydrofuran (THF), etc., a saturated hydrocarbon such as hexane, pentane, etc., a halogenated hydrocarbon such as dichloromethane, chloroform, etc., an aromatic hydrocarbon such as benzene, toluene, etc. These solvent may be used solely or in combination of two or more in an appropriate ratio. The aldehyde compound (IVe1) or (IVe2) is used in 0.5 to 10 equivalents, preferably 0.5 to 1.5 equivalents to Compound (IVb).
Compound (IVc1) or (IVc2) is allowed to alkylation to give a Compound (IVd) or (Ia), respectively. Examples of the alkylating agents (IVf) used include an alkyl halide (e.g. methyl iodide, ethyl bromide, isopropyl bromide, etc.), an ester of an alkyl or an aryl sulfonic acid (e.g. methyl methanesulfonate, ethyl p-toluenesulfonate, etc.), etc. The alkylating agent can be used in an amount of 1 to 10 equivalents, preferably 1 to 2 equivalents to Compound (IVc1) or Compound (IVc2). The reaction is usually carried out in a basic condition. Examples of the base used include sodium hydride, potassium carbonate, sodium methylate, etc. The reaction is usually carried out in an inert solvent. Examples of the solvent include, for example, dimethylformamide, an ether such as tetrahydrofuran, etc., a halogenated hydrocarbon such as dichloromethane, etc. The reaction time is usually 30 min to 24 h, preferably 30 min to 10 h though it varies depend on the activity and amount of the alkylating agent and kind of the base. The reaction temperature is usually xe2x88x9220xc2x0 C. to 150xc2x0 C.
By a similar manner to a known method, Compound (IVd) is subjected to a de-protecting reaction which removes the protecting group of A11 to give Compound (Ia). For example, Compound (IVd) wherein A11 has a trityl group, that is, the nitrogen-containing heterocyclic group which may be substituted is protected by a trityl group, the compound can be treated under acidic conditions or undergo hydrogenolysis to remove the trityl group. Examples of the acid include an organic acid such as formic acid, acetic acid, etc., an inorganic acid such as hydrochloric acid, etc. The reaction can be carried out in an inert solvent such as an alcohol, an ether (e.g. tetrahydrofuran, etc.), etc. The reaction temperature is usually 0xc2x0 C. to 100xc2x0 C. 
(wherein each symbol has the same meaning as defined above.)
Compound (IVc2) is allowed to usual oxidation reaction to give Compound (Vb). The reaction is carried out by using manganese dioxide, chromic acid, etc., as an oxidizing agent in an inert solvent such as dichloromethane, chloroform, THF, etc. The reaction time is usually 30 min to 48 h, preferably 30 min to 10 h. The reaction temperature is usually 0xc2x0 C. to 100xc2x0 C., preferably 20xc2x0 C. to 70xc2x0 C.
Compound (Vb) can be converted to Compound (II) by removing the protecting group By a similar manner to a known method. The elimination of the protecting group is carried out by a similar manner to the production of Compound (Ia) from Compound (IVd). Compound (II) is reacted with an organometal reagent (III) (an alkyl lithium reagent such as methyl lithium, etc., a Grignard reagent such as ethyl magnesium bromide, isopropyl magnesium chloride, etc.) to give Compound (Ib). The reaction can be carried out by a per se known manner or, for example, a manner shown in Shin-jikkenkagaku-koza Vol. 14, p512 (Maruzen Co. Japan) or a manner similar to these methods. The organometal reagent (III) is used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents to the ketone (II). The reaction temperature is xe2x88x92100xc2x0 C. to 50xc2x0 C., preferably xe2x88x9280xc2x0 C. to 20xc2x0 C. The reaction time is 5 min to 20 h. The reaction is usually carried out in the presence of an organic solvent which does not affect to the reaction. Examples of the organic solvent which does not affect to the reaction include, for example, an ether such as diethyl ether, dioxane, tetrahydrofuran, etc., a saturated hydrocarbon such as hexane, pentane, etc., a halogenated hydrocarbon such as dichloromethane, chloroform, etc., an aromatic hydrocarbon such as benzene, toluene, etc. These solvent may be used solely or in combination of two or more in an appropriate ratio.
Compound (Ib) can also be produced by reacting Compound (Vb) with Compound (III) to give Compound (Vd), followed by subjecting Compound (Vd) to deprotection reaction. 
[wherein Rxe2x80x2 is a group shown by the formula: ORxe2x80x3 or by the formula: NRxe2x80x3Rxe2x80x2xe2x80x3 (wherein each of Rxe2x80x3 and Rxe2x80x2xe2x80x3 is a lower alkyl group or a lower alkyloxy group. NRxe2x80x3Rxe2x80x2xe2x80x3 may be a cyclic amine residue such as a morpholino group, a pyrrolidino group, etc.), A12 is a nitrogen-containing heterocyclic group which may be protected or/and substituted, and each of the other symbols has the same meaning as defined above.]
Examples of the nitrogen-containing heterocyclic group which may be protected or/and substituted among the nitrogen-containing heterocyclic group which may be protected or/and substituted shown by A12, include the same as that mentioned about A11, and that having no protecting group is the same as that mentioned about A.
Compound (VIa) is reacted with (VIb) by known Friedel-Crafts reaction, the manner shown in Shin-jikkenkagaku-koza Vol.14, p511 (Maruzen Co. Japan) or a manner similar to those manner, to give the carbonyl compound (VIc). Compound (VIc) can also be produced by reacting Compound (IVb) with Compound (VIe). The reaction is carried out in an inert solvent such as THF, dichloromethane, etc. Compound (IVb) is used in an amount of 0.2 to 2 equivalents, preferably 0.2 to 1.5 equivalents to Compound (VIe). The reaction temperature is xe2x88x9280xc2x0 C. to 50xc2x0 C., preferably xe2x88x9280xc2x0 C. to 20xc2x0 C.
Compound (Vd) can be produced by subjecting Compound (VIc) to alkylation reaction by using Compound (VId). The reaction can be carried out by a similar manner to the production of Compound (Ib) from Compound (II).
Compound (Vd) can also be produced by reacting an organometal reagent (IVb) with a ketone (VIf) By a similar manner to the production of Compound (Ib) from Compound (II). Compound (Vd) wherein the nitrogen-containing heterocyclic group is protected can be converted to Compound (Ib) by removing the protecting group by a similar manner to the production of Compound (Ia). 
[wherein each symbol has the same meaning as defined above.]
Compound (Ic) can be produced by subjecting Compound (Vd) to alkylation reaction by using Compound (IVf) to give Compound (VIg), followed by removing the protecting group. The alkylation reaction is carried out by a similar manner to the production of Compound (IVd) from Compound (IVc2). The elimination of the protecting group is carried out by a similar manner to the production of Compound (Ia) from Compound (IVd). 
(wherein each symbol has the same meaning as defined above.)
Compound (VIa) is reacted with (VIIa) by a known Friedel-Crafts reaction, the manner shown in Shin-jikkenkagaku-koza Vol. 14, p511 (Maruzen co. Japan) or a manner similar to those manner, to give a carbonyl compound (VIIc). Compound (VIIc) can also be produced by reacting Compound (IVb) with Compound (VIIb). The reaction is carried out in an inert solvent such as THF, dichloromethane, etc. Compound (IVb) is used in an amount of 0.2 to 2 equivalents, preferably 0.2 to 1.5 equivalents to Compound (VIIb). The reaction temperature is usually xe2x88x9280xc2x0 C. to 50xc2x0 C., preferably xe2x88x9280xc2x0 C. to 20xc2x0 C.
When the desired compound is obtained in free form, the compound may be converted to a salt by a conventional manner. When the desired compound is obtained in a salt, the compound can be converted to free form by a conventional manner. Compound (I) thus obtained can be isolated from the reaction mixture and purified by a known procedure such as phase transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, etc. In the above reactions, an amino group, a carboxyl group, a hydroxy group, each of which is not involved in the reaction, in the compound or a salt thereof which is to be reacted may be protected. The protection with a protecting group and deprotection can be carried out by a known manner. Examples of the protecting group of an amino group include, for example, formyl, a C1-6alkylcarbonyl (for example, acetyl, propionyl, etc.), a phenyl carbonyl, a C1-6alkyl-oxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, a C7-10aralkyloxy-carbonyl (for example, a phenyl-C1-4alkyloxy-carbonyl such as benzyloxycarbonyl, etc.), trityl, phthaloyl or N,N-dimethylaminomethylene, etc., each of which may be substituted. Examples of the substituent include a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), formyl, a C1-6alkyl-carbonyl (for example, acetyl, propionyl, valeryl, etc.), nitro, etc. The number of substituent is about 1 to 3.
Examples of the protecting group of a carboxyl group include, for example, a C1-6alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl or silyl, etc., each of which may be substituted. Examples of the substituent include, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), formyl, a C1-6alkyl-carbonyl(for example, acetyl, propionyl, valeryl, etc.), nitro, etc. The number of substituent is about 1 to 3.
Examples of the protecting group of a hydroxy group include, for example, a C1-6alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, a C7-10aralkyl (for example, a phenyl-C1-4alkyl such as benzyl, etc.), formyl, a C1-6alkyl-carbonyl (for example, acetyl, propionyl, etc.), phenyloxycarbonyl, benzoyl, a (C7-10aralkyloxy)carbonyl (for example, a phenyl-C1-4alkyloxy-carbonyl such as benzyloxycarbonyl, etc.), pyranyl, furanyl or silyl, etc., each of which may be substituted. Examples of the substituent include a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a C1-6alkyl (for example, methyl, ethyl, propyl, etc.), phenyl, a C7-10aralkyl (for example, a phenyl-C1-4alkyl such as benzyl, etc.), nitro, etc. The number of substituent is about 1 to 4.
The deprotection reaction is carried out by a known manner or a similar manner thereof. Examples of the deprotection reaction include a manner treating with, for example, acid, base, reduction, ultraviolet ray, hydrazine, phenyl hydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc.
When Compound (I) is diastereomer, conformer, etc., Compound (I) can be isolated and purified by a isolation procedure or purification procedure mentioned above, if desirable. When Compound (I) is a racemate, (+)-form and (xe2x88x92)-form of Compound (I) can be isolated by a usual optical resolution procedure. When Compound (I) has a basic group, it can be converted to a salt with acid by a known manner.
Compound (I) has superior effect for medicine, and especially has a superior inhibitory activity of steroid C17,20-lyase. Compound (I) is less toxic and has little adverse side effect. Compound (I) is useful for the preventing and treating a mammal (for example, humans, bovines, horses, dogs, cats, monkeys, mice, rats, etc., especially humans) suffering from various disease such as (1) primary cancer of malignant tumor (for example, prostate cancer, breast cancer, uterine cancer, ovarian cancer, etc.), and its metastasis and recurrence, (2) various symptoms accompanied with these cancer (for example, pain, cachexia, etc.), (3) prostatichypertrophy, virilism, hirsutism, male pattern alopecia, precocious puberty, endometriosis, uterus myoma, adenomyosis of uterus, mastopathy, polycystic ovary syndrome, etc.
While Compound (I) has a superior effect when used solely, the effect can be promoted by using the compound (I) in combination with other medicaments and remedies. Examples of the medicament and remedy, include, for example, sex hormones, alkylating agents, antimetabolites, antitumor antibiotics, plant alkaloids, immunotherapies, etc., but not limited to.
Examples of the hormone like agent include, for example, Fosfestrol, Diethylstilbestrol, chlorotrianisene, Medroxyprogesterone acetate, Megestrol acetate, Chlormadinone acetate, Cyproterone acetate, Danazol, Allylestrenol, Gestrinone, Mepartricin, Raloxifene, Ormeloxifene, Levormeloxifene, antiestrogens (for example, Tamoxifen, Toremifene, etc.), the contraceptive pill, Mepitiostane, Testolactone, Aminoglutethimide, LH-RH agonist (for example, Goserelin acetate, Buserelin, Leuprorelin, etc.), LH-RH antagonist (for example, Ganirelix, Cetrorelix, Abarelix, etc.), Droloxifene, Epitiostanol, Ethinylestradiol sulfonate, aromatase inhibitors(for example, Fadrozole, Anastrozole, Letrozole, Exemestane, Vorozole, Formestane, etc.), anti-androgens (for example, Flutamide, Bicalutamide, Nilutamide, etc.), 5xcex1-reductase inhibitors (for example, Finasteride, Epristeride, etc.), adrenocortical hormones (for example, Dexamethasone, Prednisolone, Betamethasone, Triamcinclone, etc.), inhibitors of androgen-synthesis (for example, Abiraterone, etc.), Retinoid and suppressing agents of Retinoid metabolism (for example, Liarozole, etc.), etc.
Examples of the alkylating agents include, for example, Nitrogen mustard, Nitrogen mustard N-oxide hydrochloride, Chlorambucil, Cyclophosphamide, Ifosfamide, Thiotepa, Carboquone, Improsulphan tosilate, Busulfan, Nimustine, Mitobronitol, Melphalan, Dacarbazine, Ranimustine, Estramustine phosphate sodium, Triethylenemelamine, Carmustine, Lomustine, Streptozocin, Pipobroman, Ethoglucid, Carboplatin, Cisplatin, Miboplatin, Nedaplatin, Oxaliplatin, Altretamine, Ambamustine, Dibrospidium chloride, Fotemustine, Prednimustine, Pumitepa, Ribomustin, Temozolomide, Treosulfan, Trofosfamide, Zinostatin stimalamer, Carboquone, Adozelesin, Cystemustine, Bizelesin, etc.
Examples of the antimetabolites include, for example, Mercaptopurine, 6-Mercaptopurine riboside, Thioinosine, Methotrexate, Enocitabine, Cytarabine, Cytarabine ocfosfate, Ancitabine hydrochloride, 5-FU analogues (for example, Fluorouracil, Tegafur, UFT, Doxifluridine, Carmofur, Galocitabine, Emitefur, etc.), Aminopterin, Leucovorin calcium, Tabloid, Butocin, Calcium folinate, Calcium levofolinate, Cladribine, Emitefur, Fludarabine, Gemcitabine, Hydroxycarbamide, Pentostatin, Piritrexim, Idoxuridine, Mitoguazone, Tiazofurin, Ambamustine, etc.
Example of antitumor antibiotics include, for example, Actinomycin D, Actinomycin C, Mitomycin C, Chromomycin A3, Bleomycin hydrochloride, Bleomycin sulfate, Peplomycin sulfate, Daunorubicin hydrochloride, Doxorubicin hydrochloride, Aclarubicin hydrochloride, Pirarubicin hydrochloride, Epirubicin hydrochloride, Neocarzinostatin, Mithramycin, Sarkomycin, Carzinophilin, Mitotane, Zorubicin hydrochloride, Mitoxantrone hydrochloride, Idarubicin hydrochloride, etc.
Examples of the plant alkaloid include, for example, Etoposide, Etoposide Phosphate, Vinblastine sulfate, Vincristine sulfate, Vindesine sulfate, Teniposide, Paclitaxel, Vinorelbine, etc.
Examples of the immunotherapy (BRM) include, for example, Picibanil, Krestin, Sizofiran, Lentinan, Ubenimex, Interferons, Interleukins, Macrophage-colony stimulating factor, granules stimulating factor of spheroid colony, Erythropoietin, Lymphotoxin, BCG vaccine, Corynebacterium parvum, Levamisole, Polysaccharide-K, Procodazol, etc.
Others: L-asparaginase, Aceglatone, Procarbazine hydrochloride, Protoporphyrin, Hematoporphyrin, topoisomerase Iinhibitors (for example, Irinotecan, Topotecan, etc.), topoisomerase Iiinhibitors (for example, Sobuzoxane, etc.), differentiation promoter (for example, Retinoid, Vitamin D, etc.), inhibitor of proliferation factor (for example, Suramin, etc.), Angiogenesis inhibitors, a-broker (for example, Tamsulosin hydrochloride, etc.), Tyrosin kinase inhibitors, etc.
Examples of the other remedies include operation, thermotherapy, radiotherapy, etc. Therapies other than chemotherapies, such as an operation including orchiectomy, thermotherapy, radiotherapy, etc., can be conducted together with the administration of Compound (I).
Examples of the pharmaceutically acceptable carrier include various organic or inorganic carriers which are used as pharmaceutical ingredients. Excipients, lubricants, binders, disintegrators, thickeners can be used for solid preparations; solvents, dispersants, solubilizing agents, suspending agents, isotonic agents, buffer agents, soothing agents, etc., can be used for liquid preparations. If necessary, additives such as preservatives, antioxidants, coloring agents, sweetening agents, etc., can be used. Examples of the preferable excipient include, for example, lactose, saccharose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, etc. Examples of the preferable lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica, etc. Examples of the preferable binder include, for example, crystalline cellulose, saccharose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, etc. Examples of the preferable disintegrator include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, crosscarmelose sodium, carboxymethyl starch sodium, etc. Examples of the preferable thickener include, for example, natural rubbers, cellulose derivatives, acrylic acid polymers, etc. Examples of the preferable solvent include, for example, water for injection, alcohol, propyleneglycol, Macrogol, sesame oil, corn oil, etc. Examples of the preferable dispersant include, for example, Tween 80, HCO 60, polyethylene glycol, carboxymethylcellulose, sodium alginate, etc. Examples of the preferable solubilizing agent include, for example, polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc. Examples of the preferable suspending agent include, for example, surfactarits such as stearyl triethanolamine, sodium laurylsulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc.; for example, hydrophilic polymer such as polyvinylalcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc. Examples of the preferable isotonic agent include, for example, sodium chloride, glycerin, D-mannitol, etc. Examples of the preferable buffer agent include, for example, buffer solution such as phosphoric acid salt, acetic acid salt, carbonate, citric acid salt, etc. Examples of the preferable soothing agent include, for example, benzyl alcohol, etc. Examples of the preferable preservative include, for example, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethylalcohol, dehydroacetic acid, sorbic acid, etc. Examples of the preferable antioxidant include, for example, sulfurous acid salt, ascorbic acid, etc.
The pharmaceutical preparation of the present invention can be manufactured by a usual manner. The ratio of Compound (I) contained in a pharmaceutical preparation is usually 0.1 to 100% (w/w). Examples of the embodiment of the pharmaceutical preparation are as follows:
(1) tablets, powder, granules, capsules:
These preparations can be prepared by adding, for example, exipients, disintegrators, binders or lubricants, etc., to Compound (I), by compressive molding the mixture and if necessary, by coating for masking of taste, enteric or sustained release.
(2) injections:
These preparations can be prepared by dissolving Compound (I) in aqueous injection together with, for example, dispersants, preservatives, isotonic agents, etc., or by dissolving, dispersing or emulsifying Compound (I) in a vegetable oil such as olive oil, sesame oil, cotton seed oil, corn oil, etc., or propyleneglycol, etc., to give an oily injection.
(3) suppositories:
These preparations can be produced by preparing a liquid composition containing Compound (I), which may be oily, aqueous solid like or aqueous semisolid like. Examples of the oily base used for the composition include, for example, triglycerin ester of long-chain fatty acid (for example, cacao butter, witepsols, etc.), middle-chain fatty acid (for example, miglyols, etc.), vegetable oils (for example, sesame oil, soybean oil, cotton seed oil, etc.), etc. Examples of the aqueous gel base include, for example, natural rubber, cellulose derivative, vinyl polymer, acrylic acid polymer, etc.
The content of Compound (I) in these preparation is usually 0.01 to 50%, though it varies depending upon the kind of pharmaceutical preparation.
The rate of the compound of the present invention in the above pharmaceutical preparation, varies depending upon the compound used, kind of animal to which the compound is administered, number of administration times, etc. The daily dose of the compound of the present invention, for example, for adult humans suffering from solid tumors (a patient suffering from, for example, prostate cancer), is usually about 0.001 to about 500 mg/kg-weight, preferably about 0.1 to about 40 mg/kg-weight, more preferably about 0.5 to about 20 mg/kg-weight. When Compound (I) is non-orally administered or when it is administered in combination with an other anti-cancer agent, Compound (I) is administered in a less amount mentioned above. A dose of Compound (I) actually a administered are decided by a doctor by taking kind of compound, type of pharmaceutical preparation, age of the patient, body weight, sex, degree of disease, administration route, administration term and its interval, etc., into consideration, and the dose may be changed by a doctor.
The pharmaceutical preparation can be administered orally or parenterally. Examples of the parenteral administration route include intravenous, intramuscular, subcutaneous, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal and intraperitoneal, etc.
The above mentioned administration term and administration interval varies depending upon the various conditions and decided by a doctor. As the administration, there may be mentioned divided administration, daily administration, intermittent administration, high dose administration therapy in short term, repeat administration, etc. It is preferable to administer the compound, for example, once to some times a day (especially two or three times a day). It is possible to administer the compound once to some times a day when oral administration. It is also possible to the compound as a sustained release preparation. It is also possible to the compound by intravenous drip infusion over a long time